FIRST-LINE MANAGEMENT OF A SYMPTOMATIC LYMPHATIC LEAK
CASE 1: A newborn female with Noonan syndrome is admitted to the neonatal ICU for persistent abdominal ascites. Exam demonstrates diffuse soft tissue edema, a moderately distended abdomen, and stable vitals. Diagnostic paracentesis confirms the fluid is chylous and peripheral laboratory evaluation is notable for hypoalbuminemia, hypogammaglobulinemia and lymphocytopenia. MR lymphangiography identifies areas of likely congenital intestinal lymphangiectasia. Treatment recommendations include immediate transition to a medium-chain triglyceride diet, IV albumin repletion, and serial abdominal ultrasound surveillance to monitor rate of ascites reaccumulation. In the following 4 weeks, only one additional therapeutic paracentesis is required indicating a “low-flow” rate lymphatic leak, and the frequency of albumin replacement greatly decreases as peripheral edema resolves. After 8 weeks on a medium-chain triglyceride formula (Portagen), the fat and caloric content of her diet is slowly liberalized without further evidence of ascites or edema.
Multidisciplinary management of a symptomatic lymphatic leak centers around respiratory support, volume repletion, diet augmentation and minimally invasive attempts to treat the source of a lymphatic leak. The goal of first-line management is to encourage spontaneous and timely closure of leaking lymphatic vessels.
If the clinical scenario allows, a period of observation and medical support is indicated for both premature and term infants presenting with chylous leaks. In some instances, chylous leaks are temporary. Postnatally, lymphovenous communications can be established through collateral channels or lymph nodes (mediastinal, lumbar, renal, or hepatic) allowing chyle to regain access to the general circulation. Development of alternative lymphatic flow can take weeks to months. Patience must be incorporated into the care of congenital chylothorax and chylous ascites. Limiting frequent adjustments to treatment regimen is helpful so as to not confound the ability to interpret response to interventions.
Antenatal interventions for congenital chylous collections include serial ultrasounds, intrauterine interventions such as thoracoamniotic shunt, and rarely, intrauterine chemical pleurodesis[17]. Thoracoamniotic shunting for congenital chylothorax and reversal of hydrops significantly improves survival; prematurity portends a worse prognosis and increased mortality.[17] The longer the interval between thoracomaniotic shunting for congenital chylothorax and delivery, the more likely the reversal of hydrops and neonatal survival.[17]
Low-flow lymphatic leaks (< 500 ml/day in adults, or roughly < 20 ml/kg/day in children) may close spontaneously and/or respond to supportive care medical management. High flow lymphatic leaks (> 1 L/day in adults, or roughly > 20 ml/kg/day in children) tend to require more aggressive therapy including surgical or interventional procedures to reduce morbidity and mortality.[18] (Figure 3). Maintaining a drain until the patient is tolerating a full diet allows for monitoring of continued leak. Alternatively, serial abdominal or chest ultrasonography are utilized when necessary to monitor reaccumulation.
Drainage: In symptomatic chylous effusion, intermittent aspiration of fluid and/or placement of thoracostomy tube for continuous drainage can be necessary to improve symptoms, allow for better lung expansion, and decrease the size of potential pleural space to help seal the lymphatic leak. Despite drainage, some lymphatic leaks persist, leading to the need for chronic drainage. Mechanical ventilation is sometimes necessary. Similarly, in symptomatic chylous ascites, intermittent aspiration of fluid and/or placement of a peritoneal drain for continuous drainage may be indicated to decrease abdominal distention and improve lung expansion. Thoracentesis or peritoneal fluid aspiration allows for fluid analysis to confirm the fluid is lymphatic in origin (Table 2) .
Nutritional Management: Goals of nutritional supportive care include decrease chylous production and accumulation of effusion or ascites, maintenance of adequate nutrition and electrolytes, and protein repletion. A symptomatic chylous effusion or ascites should be monitored for twenty-four hours to establish a baseline rate of lymphatic leak. Daily weights should be documented to monitor for shifts in fluid balance.
Patients who demonstrate a “low-flow” rate (< 20 ml/kg/day) of lymphatic leak may benefit from a trial off long-chain-fats (LCF) to a medium-chain-triglyceride (MCT) based formula. Long chain fats (LCF) make up most of our dietary fat. Their digestion is complex and involves both the gastrointestinal and lymphatic systems. Chyle from intestines is a protein rich fluid - returning between one-fourth to one-half of plasma protein in circulation to the body. LCFs are ingested and released as micelles with fat in the small bowel. Here, the micelles interact with pancreatic lipase, breaking down the LCF. Micelles transport fatty acids to intestinal villi where they are absorbed. Medium chain triglycerides (MCT), however, are easily absorbed across the small intestine into the portal system without requiring transport into the lymphatic system. Because of this, a diet including MCT products should not increase the production of lymphatic fluid. Slowly, over the course of weeks, a low-fat diet associated with MCT may resolve clinical and biochemical complications. If drain output does not decrease after 1-2 weeks on MCT diet, transitioning to complete gut rest with total parenteral nutrition with or without octreotide as an adjunct should be considered.
Formulas that contain high levels of MCT include Portagen, Progestimil, and Enfaport (Table 3) . Newborns whose enteral intake consists exclusively of MCT containing formulas are at risk for developing essential fatty acid (EFA) deficiency. A fatty acid profile and fat-soluble vitamins (Vitamin A, D, E, K) should be monitored in these patients after 1-2 weeks of initiating an MCT based formula and consider adding an EFA supplement to the diet. EFA deficiency can develop within the first few weeks of a lymphatic leak and presents with skin rashes, impaired wound healing, thrombocytopenia and growth delays. Lipids are an essential part of development of the nervous system; the developmental impact limiting lipid intake may impact early brain growth. As a lymphatic leak improves, fatty acid profile should be monitored every 3 months until normalized and then every 6 months after.
In patients with a “high-flow” rate (> 20ml/kg/day) of lymphatic leak and those who are refractory to MCT formula, more aggressive nutritional restriction is indicated. Cessation of all enteral nutrition to reduce the production of chyle driven by dietary fat intake may be indicated. Total parenteral nutrition (TPN) with intravenous lipids is initiated to replete caloric and electrolyte deficiencies and improve fluid balance. Intravenous lipids are delivered directly into the blood stream, do not travel through the lymphatic system and are not contraindicated in the treatment of high-flow lymphatic leak.
Laboratory monitoring: With a symptomatic lymphatic leak, electrolyte and organ function should be evaluated with a complete metabolic panel. Protein loss can be estimated by serum albumin and IgG level. A complete blood count helps monitor progressive lymphopenia. The frequency of laboratory monitoring is relative to the rate of lymphatic loss. Whereas high-flow lymphatic loss may require metabolic panel monitoring multiple times daily, low-flow lymphatic loss often only requires once daily monitoring and frequency can be liberalized as symptoms resolve to spare cumulative blood loss.
Albumin repletion: The efficacy of albumin replacement, in general, has been controversial in critical care medicine. Although not a direct therapy for lymphatic leak, repletion of albumin is often performed when disease is complicated by serous effusions or symptomatic limb edema (third spacing). Albumin provides an increase in intravascular oncotic pressure and causes mobilization of fluids from interstitial into intravascular space. For effusions or ascites with hypoalbuminemia, 25% albumin (250 mg/ml) can be given at 1g/kg/dose infused over 2 to 3 hours. The dose can be repeated up to three times per day until the serum albumin is > 2.5 g/dL; maximum dose of 25 g/dose.[19] Side effects of an albumin infusion may include hypertension, tachycardia, fever, chills, rash, nausea and vomiting. Serial albumin infusions intravenously may reduce edema, but the impact is often transient.
Octreotide: Octreotide is a synthetic somatostatin analogue commonly used to treat secretory diarrhea, esophageal varices, and post-gastrectomy dumping syndrome. The mechanism of action of octreotide involves reduced splanchnic blood flow, portal pressure, and intestinal absorption of fats. Additionally, octreotide decreases gut motility and splanchnic lymphatic production. In the setting of high-flow or refractory lymphatic leak evidence supports the use of octreotide to reduce the rate of lymphatic leak in both congenital and acquired chylous effusion and ascites. An initial dose is commonly 1-2 mcg/kg/hour as a continuous intravenous infusion, titrating up to a clinical response with a median maximum dose of 10 mcg/kg/hour. Although octreotide can be delivered subcutaneously, there is greater evidence of efficacy in children and neonates when given intravenously. Duration of therapy commonly ranges from 7 to 14 days.[20] Congenital lymphatic leak tends to require higher doses and a longer duration of therapy compared to acquired lymphatic leak. Side effects include bradycardia, hypertension, worsening of underlying pulmonary hypertension, hyperglycemia, and headache. Octreotide may be considered immediately in patients with high-flow output with symptomatic electrolyte and protein losses, or in patients who have failed an NPO trial of 1-2 weeks.
IgG repletion: Although not a direct therapy for lymphatic leak, adjuvant IgG repletion may be necessary. IgG repletion via intravenous immunoglobulin (IVIG) should be reserved for patients actively fighting infectious complications. In this case, low dose infusions of ~400mg/kg can be given to maintain a minimal physiologic IgG. Transfused immunoglobulins are quickly depleted by continuous lymphatic leak making it difficult to maintain higher serum concentrations. In the patient without active infections, serial IVIG infusions given to improve the serum IgG value risk the introduction of a considerable fluid burden that may cause more harm to fluid balance than active benefit.
Fever management: Fluid within an effusion or ascites is at risk of becoming infected. Providers should have a low threshold to evaluate and treat febrile patients with a lymphatic leak. Consider oral antibiotic course for fever without a source and consider intravenous broad coverage antibiotics for fever with culture positive focal source. In the setting of chylous ascites, gram-negative coverage, such as a third-generation cephalosporin is generally recommended. Although the literature lacks recommendations for the initiation of Pneumocystis jiroveci pneumonia (PJP) prophylaxis in the setting of lymphatic leak, we have applied a general recommendation often used for patients with immunodeficiency; PJP prophylaxis is considered when the absolute lymphocyte count is < 500 cells/µL, or, if available, when the CD4+ T cell lymphocyte count is < 200 cells/µL.